1. Field of Invention
The present invention relates to the treatment of chronic congestive heart failure (CHF) and particulary to enhancement of exercise tolerance in chronic CHF patients.
2. Brief Description of the Prior Art
Chronic congestive heart failure (CHF) is associated with increased activity of the sympathetic nervous system. In addition, there is defective parasympathetic control and activation of numerous neurohumoral mechanisms for retention of salt and water. These neurohumoral mechanisms include the renin-angiotensin system and antidiuretic hormone. Although it is clear that the principal disturbance in CHF is the inability of the heart to perform as a pump, the clinical picture is often dominated by alterations of the systemic and pulmonary circulations resulting from the intense disturbance of autonomic function. In fact, these disturbances account for many of the symptoms associated with CHF. Further, because these compensatory mechanisms are present even when the body is at rest, the heart is prevented from returning to a more normal state.
Pharmacologic modification of the peripheral and pulmonary vascular adjustments by interruption of neurohumoral effects have been used in CHF to "unburden" the heart. The primary example has been the use of captopril, a potent vasodilator. Drugs acting primarily at the vascular neuroeffector junction (e.g., prazosin) or directly on vascular smooth muscle (i.e., nitrites, nitroprusside) have also been used. Further patients with congestive cardiomyopathy have improved with chronic administration of metopolol (Lopressor.RTM.), a cardioselective .beta.-adrenoceptor blocking drug. Swedberg et al., British Heart Journal, 44:133-142, 1980).
Clonidine, also known as 2-[(2,6-dichlorophenyl)amino]-2-imidazoline is well known as a potent antihypertensive sold under the registered Trademark CATAPRES.RTM.. It has been extensively described in the literature, including U.S. Pat. No. 3,202,660; Goodman and Gilman (Eds.), Pharmacological Basis of Therapeutics, 6th Ed, MacMillan Publishing Co., Inc., N.Y. (1980) p 797; THE MERCK INDEX, 9th Ed, Merck & Co., Inc., Rahway, N.J., U.S.A., Abstract 2352. page 797; and PHYSICIANS' DESK REFERENCE, 38th Ed, 1984, Medical Economics Company, Inc., Oradell, N.J., p 692.
Bolus intravenous injections of clonidine HCl have produced decreased sympathetic outflow, increased vagal tone and sensitivity of the baroreceptor reflex, with peak effects occurring at 5-20 minutes. Reductions were observed in heart rate, left ventricular filling pressure (preload), mean systemic arterial pressure (afterload), mean pulmonary artery pressure and right atrial pressure. Giles, T.D. et al, Acute Effects of Intravenous Clonidine HCl in Congestive Heart Failure, Circulation, II, 62(4), October 1980.